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Current Oncology Reports

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01-04-2020 | Melanoma | Melanoma (RJ Sullivan, Section Editor)

Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls

Authors: Eli P. Darnell, Meghan J. Mooradian, Erez N. Baruch, Melis Yilmaz, Kerry L. Reynolds

Published in: Current Oncology Reports | Issue 4/2020

Abstract

Purpose of Review

While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field.

Recent Findings

Knowledge of immunotherapy toxicity has continually evolved, and several major oncologic societies have recently released new or updated guidelines.

Summary

Keeping up with the evolving field of immunotherapy and related toxicities is crucial, because ICI use, in combination with other agents, will only continue to increase and likely result in new and different patterns of irAEs. Providing clear and concise references for clinicians will help ensure proper irAE evaluation and management going forward. We present one such reference here, covering management of common and/or serious irAEs.

Society AC. Cancer Facts & Figures 2019. Atlanta. http://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed 10-10-2019 2019.

Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1. https://doi.org/10.1056/NEJMc1509660.CrossRefPubMed

Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60. https://doi.org/10.1016/j.ctrv.2016.02.001.CrossRefPubMed

Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49. https://doi.org/10.3389/fphar.2017.00049.CrossRefPubMedPubMedCentral

Widmann G, Nguyen VA, Plaickner J, Jaschke W. Imaging features of toxicities by immune checkpoint inhibitors in cancer therapy. Curr Radiol Rep. 2016;5(11):59. https://doi.org/10.1007/s40134-017-0256-2.CrossRefPubMed

•• Haanen J, Carbonnel F, Robert C, Kerr K, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119–iv42. https://doi.org/10.1093/annonc/mdx225The European Society for Medical Oncology guidelines for management of immunotherapy-related toxicity across a broad range of organ systems. These were the first guidelines to be published by a major oncologic society.CrossRefPubMed

•• Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68. https://doi.org/10.1200/jco.2017.77.6385The American Society of Clinical Oncology guidelines for management of immunotherapy-related toxicity. These comprehensive guidelines, released along with the NCCN guidelines below, detail management of immunotoxicities by grade of severity.CrossRefPubMedPubMedCentral

•• Thompson J, Schneider B, Brahmer J, Andrews S, Armand P, Bhatia S et al. NCCN Guidelines Version 2.2019 Management of Immunotherapy-Related Toxicities. National Comprehensive Cancer Network, NCCN.org. 2019. Accessed 9/9/2019 2019. The National Comprehensive Cancer Network guidelines for management of immunotherapy-related toxicity. These comprehensive guidelines detail management of immunotoxicities by grade of severity with subtle differences in management recommendations from ASCO guidelines.

•• Ernstoff M, Puzanov I, Robert C, Diab A, Hersey P. SITC's Guide to Managing Immunotherapy Toxicity. Demos Medical Publishing; 2019. One of the most recently released, and comprehensive, resources for diagnosis and management of immunotherapy-related toxicity.

10.

Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8. https://doi.org/10.1001/jamaoncol.2018.3923.CrossRefPubMedPubMedCentral

11.

• Reynolds KL, Guidon AC. Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Neurologic Toxicity: Illustrative Case and Review of the Literature. Oncologist. 2019;24(4):435–43. https://doi.org/10.1634/theoncologist.2018-0359A comprehensive, and up-to-date, review of central and peripheral system neurologic irAEs, including guideline-based recommendations for management.CrossRefPubMed

12.

Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute. 2017. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed Sept 14th 2019.

13.

Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. 2017;41(2):125–8. https://doi.org/10.1016/j.currproblcancer.2016.12.001.CrossRefPubMed

14.

Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25. https://doi.org/10.1016/j.ejca.2016.02.010.CrossRefPubMedPubMedCentral

15.

Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28(4):254–63. https://doi.org/10.1097/CCO.0000000000000290.CrossRefPubMed

16.

Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44(2):158–76. https://doi.org/10.1111/cup.12858.CrossRefPubMed

17.

Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45–51. https://doi.org/10.1001/jamadermatol.2015.2707.CrossRefPubMed

18.

Quach HT, Dewan AK, Davis EJ, Ancell KK, Fan R, Ye F, et al. Association of anti-programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma. JAMA Oncol. 2019;5(6):906–8. https://doi.org/10.1001/jamaoncol.2019.0046.CrossRefPubMedPubMedCentral

19.

Lopez AT, Khanna T, Antonov N, Audrey-Bayan C, Geskin L. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 2018;57(6):664–9. https://doi.org/10.1111/ijd.13984.CrossRefPubMed

20.

Phillips GS, Wu J, Hellmann MD, Postow MA, Rizvi NA, Freites-Martinez A et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. 2019:JCO1802141. doi:https://doi.org/10.1200/JCO.18.02141.

21.

Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, et al. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7(4):405–18. https://doi.org/10.12998/wjcc.v7.i4.405.CrossRefPubMedPubMedCentral

22.

Wang Y, Abu-Sbeih H, Mao E, Ali N, Qiao W, Trinh VA, et al. Endoscopic and histologic features of immune checkpoint inhibitor-related colitis. Inflamm Bowel Dis. 2018;24(8):1695–705. https://doi.org/10.1093/ibd/izy104.CrossRefPubMed

23.

Dougan M. Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal tract. Front Immunol. 2017;8:1547. https://doi.org/10.3389/fimmu.2017.01547.CrossRefPubMedPubMedCentral

24.

Hughes MS, Zheng H, Zubiri L, Molina GE, Chen ST, Mooradian MJ, et al. Colitis after checkpoint blockade: a retrospective cohort study of melanoma patients requiring admission for symptom control. Cancer Med. 2019. https://doi.org/10.1002/cam4.2397.

25.

Geukes Foppen MH, Rozeman EA, van Wilpe S, Postma C, Snaebjornsson P, van Thienen JV, et al. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open. 2018;3(1):e000278. https://doi.org/10.1136/esmoopen-2017-000278.CrossRefPubMedPubMedCentral

26.

Reynolds K, Thomas M, Dougan M. Diagnosis and management of hepatitis in patients on checkpoint blockade. Oncologist. 2018;23(9):991–7. https://doi.org/10.1634/theoncologist.2018-0174.CrossRefPubMedPubMedCentral

27.

Cohen JV, Misdraji J, Dougan M, Fadden R, Rubin KM, Lawless A, et al. Characterization of immune related hepatitis (irH) from immune checkpoint inhibitors (ICIs). J Clin Oncol. 2018;36(15_suppl):3087. https://doi.org/10.1200/JCO.2018.36.15_suppl.3087.CrossRef

28.

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.CrossRefPubMedPubMedCentral

29.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. https://doi.org/10.1056/NEJMoa1504030.CrossRefPubMedPubMedCentral

30.

Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375–91. https://doi.org/10.1093/annonc/mdv383.CrossRefPubMedPubMedCentral

31.

Gupta K, Afonin KA, Viard M, Herrero V, Kasprzak W, Kagiampakis I, et al. Bolaamphiphiles as carriers for siRNA delivery: from chemical syntheses to practical applications. J Control Release. 2015;213:142–51. https://doi.org/10.1016/j.jconrel.2015.06.041.CrossRefPubMedPubMedCentral

32.

Chalan P, Di Dalmazi G, Pani F, De Remigis A, Corsello A, Caturegli P. Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Investig. 2018;41(6):625–38. https://doi.org/10.1007/s40618-017-0778-8.CrossRef

33.

Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70–6. https://doi.org/10.1016/j.ctrv.2017.06.002.CrossRefPubMed

34.

McMillen B, Dhillon MS, Yong-Yow S. A rare case of thyroid storm. BMJ Case Rep. 2016;2016:https://doi.org/10.1136/bcr-2016-214603.

35.

Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 2015;38(9):e137–8. https://doi.org/10.2337/dc15-0889.CrossRefPubMed

36.

Godwin JL, Jaggi S, Sirisena I, Sharda P, Rao AD, Mehra R, et al. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J Immunother Cancer. 2017;5(1):40. https://doi.org/10.1186/s40425-017-0245-2.CrossRefPubMedPubMedCentral

37.

de Filette JMK, Pen JJ, Decoster L, Vissers T, Bravenboer B, Van der Auwera BJ, et al. Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review. Eur J Endocrinol. 2019. https://doi.org/10.1530/EJE-19-0291.

38.

Torino F, Corsello SM, Salvatori R. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol. 2016;28(4):278–87. https://doi.org/10.1097/cco.0000000000000293.CrossRefPubMed

39.

Faje A, Reynolds K, Zubiri L, Lawrence D, Cohen J, Sullivan R, et al. Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis. Eur J Endocrinol. 2019. https://doi.org/10.1530/EJE-19-0238.

40.

Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55. https://doi.org/10.1056/NEJMoa1611299.CrossRefPubMedPubMedCentral

41.

Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018;124(18):3706–14. https://doi.org/10.1002/cncr.31629.CrossRefPubMed

42.

Lee H, Hodi FS, Giobbie-Hurder A, Ott PA, Buchbinder EI, Haq R, et al. Characterization of thyroid disorders in patients receiving immune checkpoint inhibition therapy. Cancer Immunol Res. 2017;5(12):1133–40. https://doi.org/10.1158/2326-6066.CIR-17-0208.CrossRefPubMedPubMedCentral

43.

Kotwal A, Haddox C, Block M, Kudva YC. Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes. BMJ Open Diabetes Res Care. 2019;7(1):e000591. https://doi.org/10.1136/bmjdrc-2018-000591.CrossRefPubMedPubMedCentral

44.

• Suresh K, Psoter KJ, Voong KR, Shankar B, Forde PM, Ettinger DS, et al. Impact of Checkpoint Inhibitor Pneumonitis on Survival in NSCLC Patients Receiving Immune Checkpoint Immunotherapy. J Thorac Oncol. 2019;14(3):494–502. https://doi.org/10.1016/j.jtho.2018.11.016A retrospective cohort study of outcomes in patients with NSCLC treated with ICI therapy. This study found that 39% of patients developed checkpoint inhibitor pneumonitis (CIP). Among those who developed CIP, combination ICI therapy (CTLA-4 and PD-1 inhbitor) was associated with poorer survival.CrossRefPubMed

45.

Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709–17. https://doi.org/10.1200/JCO.2016.68.2005.CrossRefPubMed

46.

• Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. https://doi.org/10.1016/j.jacc.2018.02.037An observational study of ICI-related myocarditis based on data from an 8-center registry of ICI-related myocarditis cases. Prevelance, response to steroid treatment, and clinical outcomes were compared to a control group of patients. This is one of the largest studies to focus specifically on ICI-related myocarditis.CrossRefPubMedPubMedCentral

47.

Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579–89. https://doi.org/10.1016/S1470-2045(18)30608-9.CrossRefPubMedPubMedCentral

48.

Roth ME, Muluneh B, Jensen BC, Madamanchi C, Lee CB. Left ventricular dysfunction after treatment with ipilimumab for metastatic melanoma. Am J Ther. 2016;23(6):e1925–e8. https://doi.org/10.1097/MJT.0000000000000430.CrossRefPubMed

49.

Weinstock C, Khozin S, Suzman D, Zhang L, Tang S, Wahby S, et al. U.S. Food and Drug Administration approval summary: atezolizumab for metastatic non-small cell lung Cancer. Clin Cancer Res. 2017;23(16):4534–9. https://doi.org/10.1158/1078-0432.CCR-17-0540.CrossRefPubMed

50.

Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55. https://doi.org/10.1056/NEJMoa1609214.CrossRefPubMedPubMedCentral

51.

Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ, et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019;380(24):2377–9. https://doi.org/10.1056/NEJMc1901677.CrossRefPubMed

52.

Moreira A, Loquai C, Pfohler C, Kahler KC, Knauss S, Heppt MV, et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106:12–23. https://doi.org/10.1016/j.ejca.2018.09.033.CrossRefPubMed

Title: Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls
Authors: Eli P. Darnell
Meghan J. Mooradian
Erez N. Baruch
Melis Yilmaz
Kerry L. Reynolds
Publication date: 01-04-2020
Publisher: Springer US
Keywords: Melanoma
Melanoma
Myocarditis
Hepatitis
Hypophysitis
Checkpoint Inhibitors
Hypothyroidism
Published in: Current Oncology Reports / Issue 4/2020
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI: https://doi.org/10.1007/s11912-020-0897-9

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